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      The Changing Landscape of Molecular Diagnostic Testing: Implications for Academic Medical Centers


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          Over the last decade, the field of molecular diagnostics has undergone tremendous transformation, catalyzed by the clinical implementation of next generation sequencing (NGS). As technical capabilities are enhanced and current limitations are addressed, NGS is increasingly capable of detecting most variant types and will therefore continue to consolidate and simplify diagnostic testing. It is likely that genome sequencing will eventually serve as a universal first line test for disorders with a suspected genetic origin. Academic Medical Centers (AMCs), which have been at the forefront of this paradigm shift are now presented with challenges to keep up with increasing technical, bioinformatic and interpretive complexity of NGS-based tests in a highly competitive market. Additional complexity may arise from altered regulatory oversight, also triggered by the unprecedented scope of NGS-based testing, which requires new approaches. However, these challenges are balanced by unique opportunities, particularly at the interface between clinical and research operations, where AMCs can capitalize on access to cutting edge research environments and establish collaborations to facilitate rapid diagnostic innovation. This article reviews present and future challenges and opportunities for AMC associated molecular diagnostic laboratories from the perspective of the Partners HealthCare Laboratory for Molecular Medicine (LMM).

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          Utility of whole‐exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care

          An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole‐exome sequencing (WES), are identifying the genetic basis of disease for 25–40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation‐wide effort to identify mutations for childhood‐onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.
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            Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing.

            Next-generation sequencing is changing the paradigm of clinical genetic testing. Today there are numerous molecular tests available, including single-gene tests, gene panels, and exome sequencing or genome sequencing. As a result, ordering physicians face the conundrum of selecting the best diagnostic tool for their patients with genetic conditions. Single-gene testing is often most appropriate for conditions with distinctive clinical features and minimal locus heterogeneity. Next-generation sequencing-based gene panel testing, which can be complemented with array comparative genomic hybridization and other ancillary methods, provides a comprehensive and feasible approach for heterogeneous disorders. Exome sequencing and genome sequencing have the advantage of being unbiased regarding what set of genes is analyzed, enabling parallel interrogation of most of the genes in the human genome. However, current limitations of next-generation sequencing technology and our variant interpretation capabilities caution us against offering exome sequencing or genome sequencing as either stand-alone or first-choice diagnostic approaches. A growing interest in personalized medicine calls for the application of genome sequencing in clinical diagnostics, but major challenges must be addressed before its full potential can be realized. Here, we propose a testing algorithm to help clinicians opt for the most appropriate molecular diagnostic tool for each scenario.
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              Assessing copy number from exome sequencing and exome array CGH based on CNV spectrum in a large clinical cohort.

              Detection of copy-number variation (CNV) is important for investigating many genetic disorders. Testing a large clinical cohort by array comparative genomic hybridization provides a deep perspective on the spectrum of pathogenic CNV. In this context, we describe a bioinformatics approach to extract CNV information from whole-exome sequencing and demonstrate its utility in clinical testing.

                Author and article information

                Role: Academic Editor
                J Pers Med
                J Pers Med
                Journal of Personalized Medicine
                27 January 2016
                March 2016
                : 6
                : 1
                : 8
                [1 ]Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Boston, MA 02139, USA; hrehm@ 123456partners.org (H.L.R.); eduffy1@ 123456mgh.harvard.edu (E.H.)
                [2 ]Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
                [3 ]Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
                Author notes
                [* ]Correspondence: bfunke@ 123456partners.org ; Tel.: +1-617-768-8467
                © 2016 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

                : 21 October 2015
                : 21 January 2016

                molecular diagnostics,next generation sequencing,academic medical centers,laboratory of molecular medicine,partners healthcare,comprehensive testing,laboratory–physician collaborations,clinical translational research,biobank,commercial–academic partnerships


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